It is very challenging and significant to research and develop antitumor drugs in the field of life science. In recent years, with the rapid development in molecular biology and deeper understanding on occurrence, development and mechanism of cancer, various basic processes, such as signal transduction in a malignant tumor cell, modulation of cell cycle, induction of apoptosis, angiogenesis and interaction between cell and extracellular matrix, are gradually elucidated. Therefore, it is one of the important areas in pharmaceutical research and development to look for novel antitumor drugs with high efficiency, low toxicity, and strong specificity, which selectively act on specific targets. Therefore, it leads to a new antitumor drug field—molecular targeted drugs.
Molecular targeted drugs refer to a class of drugs that are directed to receptors involved in cell cancerization or to key enzymes in transduction, and inhibit tumor growth in molecular level. They target the characteristic molecules of tumor cells, and play an antitumor role whilst reducing the toxic and side-effect on normal cells.
The balance between positive and negative regulators controls the angiogenesis of tumor, which promotes the growth and metastasis of tumor, thereby the development of angiogenesis inhibitors becomes one of hotspots in tumor research. VEGFR refers to a class of important tyrosine kinases. Many studies show that dysfunction in signal transduction pathway of VEGFR plays an important role in occurrence, growth and metastasis of tumor. VEGFR mainly include VEGFR21(Flt21), VEGFR22(KDR/Flt21) and VEGFR23(Flt24), which belong to tyrosine kinase receptors. VEGF exerts biological function by binding to two trans-membrane receptors of endothelial cell.
Signal transduction factors in cell differentiation include a lot of protein kinase families. During cell signal transduction, protein tyrosine kinases are very important as they can catalyze the transfer of a phosphate group from ATP to tyrosine residue of many important proteins to make them phosphorylated, which activates transduction by-pass, and affects cell growth, proliferation and differentiation. In many tumor cells, tyrosine kinase activity is abnormally increased. More than 50% oncogenes and products thereof have protein tyrosine kinase activity, and abnormal expression thereof would lead to the occurrence of tumor. In addition, the abnormal expression of the enzyme is also associated with tumor metastasis, tumor angiogenesis, and resistance of tumor to chemical therapy. Research on selective protein kinase inhibitors that can block or modify abnormal signal transduction is deemed to be a promising direction for development of drugs. Now, some protein kinase inhibitors and small-molecule therapeutic agents against different ATP-binding sites of protein kinases have been discovered and entered a clinic research phase, such as tyrosine kinase inhibitors.
Sorafenib (Trade name: Nexavar) developed by Bayer Pharmaceuticals is a multi-targeted drug approved as the first-line drug for treatment of advanced renal carcinoma by United States Food and Drug Administration (FDA) in December, 2005, and is the first multi-targeted drug approved for targeted therapy in clinic in the world. The Chinese patent application document CN1341098A discloses the chemical structure of Sorafenib, and the structure of Sorafenib is as follows:

Before the invention, the inventor also submitted another Chinese patent application, and the patent application document CN102532113A (Application No.: 201110435847.9) discloses a compound of the following formula:

Since the existing antitumor drugs still fail to meet the needs of treating tumor diseases in human and other mammals, and the therapeutic effects of the commercially available antitumor drugs in clinic still fail to reach the desired level, there is still demand for more effective antitumor drugs.